Novel insights into the molecular pathogenesis of gastric MALT lymphoma

[摘要] Gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue(MALT lymphoma) represents a distinct class of extranodal lymphoma that evolves against abackground of chronic inflammation induced by persistent infection with the bacteriumHelicobacter pylori. In its early stages, MALT lymphoma is an antigen-dependent diseasecharacterised by an indolent clinical course and in most cases is treatable by antibioticeradication therapy alone. Low grade MALT lymphomas can eventually undergo high gradetransformation to a more aggressive counterpart termed gastric diffuse large B-celllymphoma (gDLBCL). At this stage the lymphomas grow autonomously and are refractory toHelicobacter eradication therapy. Little is known about the molecular mechanisms governingthe development of low grade MALT lymphoma and its ultimate progression to gDLBCL.To improve our current understanding of the molecular pathogenesis of MALT lymphoma, amultidimensional approach was taken to investigate various aspects of this disease during thecourse of my PhD thesis.Although a variety of circumstantial evidence has implicated an important role forantigen in MALT lymphomagenesis, the identity of such ligands recognised by the tumourcells remain unclear. To address this issue of antigen-receptor specificity, enzymeimmunoassays were employed to systematically analyse the antigen binding profile of acomprehensive panel of human and murine recombinant MALT lymphoma-derivedantibodies. The majority of tumour derived immunoglobulins were found to exhibit a broadreactivity profile in line with the definition of polyreactivity. In addition, using the BALB/cmouse model of Helicobacter-induced gastric MALT lymphoma, we demonstrated thatexplanted tumour cells proliferated in response to a variety of cognate antigens recognised bytheir polyreactive B-cell receptor. Our results therefore suggest that MALT lymphomadevelopment may be facilitated by an array of local self- and foreign antigens, providingdirect antigenic stimulation of the tumour cells via their B-cell receptor.A characteristic feature of gastric MALT lymphomas is that they are typicallyinfiltrated by large numbers of T-helper cells producing interleukin-4 (IL4) and other Thelper cell type 2 cytokines. Therefore, an additional aim of this study was to elucidate thepathogenic role of the tumour-infiltrating T-cell population. Tumour cell proliferation wasstrongly enhanced by the presence of intratumoural CD4+ T cells in a CD40/CD40Lindependentmanner. Another key finding was that a substantial fraction of tumourinfiltratingCD4+ T cells were functional CD25+FoxP3+ regulatory T (Treg) cells. These cellswere found to be recruited by the tumour cells themselves through secretion of the Tregattractingchemokines CCL17 and CCL22. Interestingly, the depletion of CD25+ T cells wasas efficient as CD4+ T-cell depletion in blocking tumour growth ex vivo and in vivo. Judgingfrom our data, we propose that MALT lymphoma cells require at least two independentsignals for proliferation. One signal is received by the functional surface-bound polyreactiveimmunoglobulin, while the other signal is delivered by tumour-infiltrating T cells, inparticular by Tregs, which are likely to play a direct role in stimulating tumour growth.To date, MALT lymphoma research has largely focused on altered expression ofprotein coding genes. However, recent evidence suggests that alterations of non-codingRNA, particularly microRNA (miRNA), also contribute to tumourigenesis. Using a genomewidemicroarray-based approach, we defined the unique miRNA expression signatureassociated with the development and progression of this disease. A special focus was firstlaid upon miR-203 and its putative tumour suppressive function during the progression fromreactive Helicobacter-specific gastritis to MALT lymphoma. We identified miR-203 to besignificantly downregulated in MALT lymphoma tissue due to hypermethylation of the miR-203 locus. The restoration of miR-203 expression in primary MALT lymphoma cellsrepressed the recently identified miR-203 target, ABL1, and blocked tumour cellproliferation. Finally, pharmacological inhibition of ABL1 activity by imatinib blockedMALT lymphoma cell proliferation ex vivo and effectively eradicated tumours in vivo.Collectively, our observations suggest that ABL1 plays an important role in MALTlymphoma cell biology and support a novel potential application of imatinib in the treatmentof MALT lymphoma.Our genome-wide survey further revealed a characteristic set of MYC-repressedmiRNAs to be specifically downregulated in human gDLBCL compared to MALT lymphoma and gastritis. Aberrant MYC expression indeed correlated with high gradetransformation as evident from our tissue microarray analysis. The re-expression of a panelof selected MYC-associated miRNAs significantly reduced the proliferation of DLBCL cells.In particular, miR-34a was found to represent the most potent tumour suppressor in DLBCLcell lines. We could further attribute the tumour suppressive effects of miR-34a todysregulation of its target FOXP1. Accordingly, FOXP1 overexpression was found to bestrongly associated with gDLBCL and the transient knockdown of FOXP1 in DLBCL celllines significantly impaired the proliferation of the tumour cells. Taken together, our findingselucidate a novel mechanism linking the aberrant expression of MYC and concomitantrepression of miR-34a to FOXP1 deregulation in high grade transformation of MALTlymphoma.

[发布机构] University of Zurich

[效力级别] 570 Life sciences

[关键词] Institute of Molecular Cancer Research;570 Life sciences;biology